Materials of animal origin are utilized in a variety of ways in the development and production of medical devices, such as bovine/porcine heart valves and hemostatic sponges, as product coating (i.e. heparin) or in the form of tallow derivatives in the device manufacturing process. Although there may be many benefits to utilizing materials of animal origin in a medical device, the regulatory requirements for manufacturers that incorporate materials of animal origin into their devices have always been challenging, and under the new EU MDR this is no exception.
The key risks of utilizing materials of animal origin in devices include infection from transmissible agents (such as viruses, bacteria, TSE agents), and undesired pyrogenic, immunological, or toxicological reactions. Therefore, the risks must be strictly controlled via selection of source material with a demonstrated minimal contamination with transmissible agents. This is usually provided by evidence within the production process that demonstrates the ability of the process to remove or inactivate contamination.
Aside from the MDR (specifically GSPR 12, 13.2 (Annex I) and Annexes XIV, XV), legislation and guidance to assist medical device manufacturers in navigating how to minimize these risks include EN ISO 22442 Parts 1-3 and Commission Regulation (EU) No. 722/2012. While EN ISO 22442 is applicable to all tissues of animal origin (excluding human), European Regulation EU 722/2012 is applicable specifically to tissues originating from TSE-susceptible species (bovine, ovine, caprine, deer, elk, mink, cats). Regulation EU 722/2012 replaces Directive 2003/32/EC and excludes devices that do not contact the human body or contact intact skin only. Compliance to both MDR and EU 722/2012 must be demonstrated by the legal manufacturer directly, irrespective of outsourcing of supply/manufacture of animal tissue components or the device itself.
Under Rule 18 of the MDR, the wording has changed from the MDD to include devices utilizing cells or tissues of human or animal origin, or their derivatives, which are non-viable or rendered non-viable. The term ‘’utilizing’’ now implies that this biological tissue does not necessarily need to be incorporated into the final device; it can be part of the manufacturing process only (as contaminants may remain on or in the device, even if the animal tissue material itself has been removed from the final device).
These devices are still classified at the highest level as Class III, meaning they are subject to the consultation process under Regulation EU 722/2012 and MDR GSPR 13.2(c) and Annex VII 4.5.6. The steps of the consultation process are described in the Regulation EU 722/2012, and these have not changed under the MDR. The manufacturer should supply the Notified Body with technical documentation that demonstrates the benefits of the device outweigh the residual risks. This documentation should include:
- Risk assessment following EN ISO 22442-2
- Justification for the use of animal tissues or derivatives (taking into consideration lower risk tissues or synthetic alternatives)
- Results of elimination and inactivation studies, or results of the analysis of relevant literature
- Manufacturer’s control of the sources of raw materials, finished products, production process, testing and subcontractors
- The need to audit matters related to the sourcing and processing of animal tissues and derivatives, processes to eliminate or inactivate pathogens, including those activities carried out by suppliers
Although released under the MDD, the MEDDEV 2.11/1 Rev. 2 guidance is currently the only available process that the Notified Bodies (NBs) may follow, and it is not currently expected to change even though it is not directly applicable to the MDR. Therefore, per this guidance, the Notified Body will review this documentation and prepare a Summary Evaluation Report (SER), which will characterize the TSE hazard, estimate risk and outline applicable risk control measures. This is submitted to the coordinating Competent Authority (CA), which will then inform the other member state CAs and the EU Commission. The NB will have to review any comments made by the CAs and give them consideration. The Notified Body must justify if comments are not considered and convey the final decision to the coordinating CA before issuing a certificate.
Starting (animal) materials that were already certified by the European Directorate for the Quality of Medicines and Healthcare (EDQM) via a Certificate of Suitability (CEP) were previously exempted from consultation with all EU member states under Directive 2003/32/EC, but are now subject to a mandatory, albeit expedited (4 weeks), consultation process under Regulation EU 722/2012. In practice, ‘’holding questions’’ may extend this timeframe. Additionally, without a CEP, the consultation process may take 12 weeks or longer.
Some animal-derived products may potentially contain an Active Pharmaceutical Ingredient (API), i.e. an RGD peptide in collagen that has an effect on blood coagulation. Although medicinal components in devices is a subject that requires separate attention, it is important to highlight that the MDR has removed the phrase of ‘liable to act on the human body’ from Rule 14 regarding medicinal products, so careful consideration must be made early in the MDR gap assessment and interaction with the NB will be warranted if APIs are present in any animal tissue-containing or derived medical devices.
In conclusion, although animal tissue devices and derived components of devices were already classified as Class III under the MDD with a high level of scrutiny by authorities, it is worth noting that manufacturers should have an upfront understanding of regulatory expectations set out by the various legislation and guidance. Animal tissue is still a high-risk component that requires strategic planning early in the product development and regulatory submission process. It is necessary to get clarity from the Notified Body if they will use the existing review of the SER that was last done under the MDD, and whether they will apply the results when they issue an MDR certificate for legacy products. The risk management and other sections of manufacturers’ Technical Documentation should be updated to align with MDR Annex I and Annex II, which may potentially give rise to a change in content of the technical documentation provided to the Notified Body, regarding the benefits/risks of the animal tissue component, and consequently to the SER. If the SER does undergo any such relevant changes, or if the benefit:risk assessment is reevaluated, the consultation process will be applicable again.
At Qserve, we have the expertise and are available to support you with all specific considerations you may need regarding animal tissue components and derivatives.